By Chris Berrie
BARCELONA, SPAIN -- June 15, 2007 -- Febuxostat, a novel, nonpurine, selective inhibitor of xanthine oxidase, achieves significantly greater reduction of serum urate (sUA) levels compared with allopurinol or placebo in older patients with gout and hyperuricemia, according to a subanalysis of two randomized controlled trials.
The results were presented here on June 14th at the Annual European Congress of Rheumatology (EULAR).
"The basic problem in gout is that you accumulate excess uric acid in the body, and the best way of getting rid of that uric acid is to block its production," indicated principal investigator Ralph Schumacher, MD, professor of medicine, department of rheumatology, University of Pennsylvania, and head of rheumatology, VA Medical Center, Philadelphia, Pennsylvania.
As this uric acid is produced by an enzyme called xanthine oxidase, both allopurinol and febuxostat have been used to target this problem in their roles as xanthine oxidase inhibitors.
However, allopurinol also displays a range of hypersensitivity reactions. In particular, this can cause problems for patients with kidney disease due to clearance of the uric acid through this organ. "The reason why febuxostat is of interest is that it is not primarily secreted by the kidney, and it is a totally different molecule," Dr. Schumacher said.
The objective was thus to determine the efficacy of different doses of febuxostat versus placebo and allopurinol in the treatment of hyperuricemia in elderly patients with gout, as a subanalysis of two randomized phase 3 clinical trials -- Febuxostat vs Allopurinol Controlled Trial (FACT) and A Phase III Randomized, Multicenter Allopurinol and Placebo-Controlled Study Assessing the Safety and Efficacy of Oral Febuxostat in Subjects with Gout (APEX).
Of 1,832 patients who participated in these two clinical trials, 295 satisfied the entry criteria for the subanalysis, with a mean age of 70.6 years, mean body mass index (BMI) of 30.8 kg/m2, aged 65 years or older, and with sUA level of 8.0 mg/dL or greater (male, 84.4%).
These patients had gout for a mean of 15.4 years, 79.3% had a flare within the previous year, 9.2% had a history of renal calculi, and 26.5% had a history/presence of tophus. Their mean baseline sUA level was 9.62 mg/dL (range, 7.3-16.1), and 32% had sAU levels at 10.0 mg/dL or greater.
As expected for an elderly population, patients had a range of comorbid conditions, including hypertension (71.2%), cardiovascular disease (32.9%), hyperlipidemia (46.1%), hypercholesterolemia (6.8%), diabetes (15.9%), and congestive heart failure (6.8%).
Patients had been randomized within these two clinical trials to receive placebo or once-daily febuxostat at a dose of 80 mg, 120 mg, or 240 mg, or once-daily allopurinol at 100 mg or 300 mg. For gout flare prophylaxis during the first 8 weeks of these trials, patients received naproxen 250 mg twice daily or colchicines 0.6 mg once daily.
Primary endpoints were the proportion of patients with sAU levels less than 6.0 mg/dL both at their last three visits and at their final visit.
The five study groups were comprised of 19 patients on placebo, 80 on febuxostat 80 mg (F80), 83 on 120 mg (F120), and 30 on 240 mg (F240); 83 patients received allopurinol 100/200 mg (A200; 3 on 100 mg, 80 on 200 mg). Baseline characteristics across these five treatment groups were all similar.
None of the patients in the placebo group satisfied the specified endpoints for sUA <6.0 mg/dL. In the A200 treatment group, for the last three patient visits and at the final patient visit, respectively, these endpoints were satisfied for a significantly greater proportion over the placebo group, at 46% and 66% (P <=.01 for both).
Febuxostat treatment satisfied the two endpoints by significantly greater proportions of patients than seen with placebo and with allopurinol at all doses (F80, 72%, 94%; F120, 78%, 89%; F240, 77%, 100%; P <= 01 in all cases)
When analyzed for adverse events, and with no dose-related effects seen across the febuxostat treatment groups, adverse events were reported by 74% of patients in the placebo group, 74% in the combined febuxostat groups, and 89% in the allopurinol group. Of these, the five most frequently reported were upper respiratory tract infections, diarrhea, musculoskeletal and connective tissue signs and symptoms, joint-related signs and symptoms, and pain and discomfort.
A total of 28 patients (9.5%) reported serious adverse events, of which the most common was cardiovascular disorders (11; 4%), but none were judged to be treatment related. Of note, all of the patients who experienced a cardiovascular adverse effect had a history of cardiovascular disorders and/or risk factors.
Dr. Schumacher noted that this is the first subanalysis of such randomized controlled trial data for patients over the age of 65 with gout and hyperuricemia. He also indicated that as a new agent for the selective inhibition of xanthine oxidase, febuxostat is significantly more effective in reducing patient sUA levels when compared with standard allopurinol treatment.
This study was sponsored by Tap Pharmaceutical Products Inc.
[Presentation title: Febuxostat Versus Allopurinol in the Treatment of Gout in Subjects 65 Years of Age or Older. Abstract THU0353]
E-Mail this DGDispatch to a colleague
